Aß Pathology and Neuron-Glia Interactions: A Synaptocentric View

Abstract

Alzheimer's disease (AD) causes the majority of dementia cases worldwide. Early pathological hallmarks include the accumulation of amyloid-ß (Aß) and activation of both astrocytes and microglia. Neurons form the building blocks of the central nervous system, and astrocytes and microglia provide essential input for its healthy functioning. Their function integrates at the level of the synapse, which is therefore sometimes referred to as the "quad-partite synapse". Increasing evidence puts AD forward as a disease of the synapse, where pre- and postsynaptic processes, as well as astrocyte and microglia functioning progressively deteriorate. Here, we aim to review the current knowledge on how Aß accumulation functionally affects the individual components of the quad-partite synapse. We highlight a selection of processes that are essential to the healthy functioning of the neuronal synapse, including presynaptic neurotransmitter release and postsynaptic receptor functioning. We further discuss how Aß affects the astrocyte's capacity to recycle neurotransmitters, release gliotransmitters, and maintain ion homeostasis. We additionally review literature on how Aß changes the immunoprotective function of microglia during AD progression and conclude by summarizing our main findings and highlighting the challenges in current studies, as well as the need for further research.

Keywords: Alzheimer’s disease; Amyloid-ß; Astrocyte; Glia; Microglia; Synapse.

Fig. 1

Pathological hallmarks of AD include the presence of Aβ plaques, and reactivity of astrocytes and microglia. a An Aβ plaque (red) surrounded by reactive astrocytes in the stratum radiatum (SR) of a 9-month-old APPswe/PSEN1dE9 mouse. Activated astrocytes (white) undergo clear cytoskeletal changes in response to Aβ pathology. b An Aβ plaque (red) surrounded by activated microglia (white) in the SR of a 9-month-old APPswe/PSEN1dE9 mouse. Microglia respond to Aβ pathology and are actively involved in clearing Aβ due to their phagocytotic capacity. Hoechst nuclei staining is indicated in blue. Scale bars: 50 µm

Fig. 2

Aβ accumulation affects pre- and postsynaptic neurotransmission. Aβ stimulates presynaptic RyR, voltage-gated Ca²⁺ channel, and α7-nAChR activity. This increases the presynaptic [Ca²⁺]. Short-term fluctuations in the presynaptic [Ca²⁺] promote kinase (K) activity and stimulate neurotransmitter release. Long-term [Ca²⁺] increases result in presynaptic depression and a subsequent decrease in neurotransmitter (i.e., glutamate) release. More advanced stages of Aβ pathology are associated with enhanced GABA release and thus, an increase in tonic neuronal network inhibition. Aβ accumulation has furthermore been shown to affect axonal transport and presynaptic d-serine release. Postsynaptically, Aβ stimulates NMDAR and AMPAR subunit phosphorylation. This initially promotes NMDAR and AMPAR expression and conductance. Aβ additionally binds and activates postsynaptic α7-nAChRs. Subsequent increases in the postsynaptic [Ca²⁺] stimulate kinase activity and activate downstream pathways and gene expression important for synaptic plasticity induction and maintenance. Prolonged increases in the postsynaptic [Ca²⁺] stimulate endocytosis, ubiquitination, and degradation of NMDARs and AMPARs. The subsequent reduction in NMDAR and AMPAR expression and function results in postsynaptic depression and a reduction in gene transcription important for synaptic plasticity induction. Figure was created with the help of BioRender.com

Fig. 3

Dysregulation of cellular processes in reactive astrocytes. The figure illustrates a reactive astrocyte displaying differentially regulated processes in response to Aβ pathology. Aβ pathology does not only impact astrocyte function at the single-cell level, but affects the entire astrocyte network. Long-term astrocyte reactivity is associated with a pro-inflammatory transcriptional profile and the decreased expression of neuronal support genes. Functionally, reactive astrocytes display an increase in calcium-wave signaling, which is associated with the increased release of gliotransmitters, including glutamate and GABA. Reactive astrocytes additionally upregulate the expression of several receptors which further stimulates gliotransmitter release. Simultaneously, reactive astrocytes downregulate the expression of glutamate transporters (GLAST/GLT-1), which promotes the presence of glutamate in the synapse. This is further stimulated by the decreased expression of GS. Astrocytes are furthermore important for maintenance of the K⁺ homeostasis and its dysfunction has been implicated in more advanced stages of AD progression, characterized by the decreased expression of Kir4.1 mRNA and impaired gap-junction coupling. In early-stage AD, however, reactive astrocytes ameliorate disease progression by the upregulation of Kir4.1 protein expression near Aβ-plaque enriched areas and protect against Aβ pathology through their active participation in Aβ clearance and the formation of a protective border surrounding the Aβ plaque. Figure was created with the help of BioRender.com

Fig. 4

Microglia are highly dynamic throughout various physiological states. Homeostatic microglia monitor the ingress of pathogens and interact directly with neurons, which is essential for regulating synaptic plasticity. Threats to the structural and functional integrity of the CNS may lead to microglial polarization towards various activated states. The presence of anti-inflammatory cytokines in the microenvironment pushes microglia towards an anti-inflammatory state, which is essential in the resolution of the immune response. In AD, microglia initially participate in Aβ clearance through their phagocytotic capacity. However, the continued exposure to soluble and oligomeric Aβ induces a pro-inflammatory microglial response through TLR, NLRP3 inflammasome, and NF-κB signaling. These microglia release pro-inflammatory cytokines that affect the capability of neurons to induce synaptic plasticity via the activation of downstream pathways involving P38 MAPK and c-Jun N terminal kinase signaling and activation of the JAK/STAT pathway. Moreover, microglia lose their potential to mount an anti-inflammatory response as a result from Aβ accumulation. DAM are microglia specifically associated with Aβ-plaque pathology in AD. DAM are neuroprotective in the initial stages of AD pathology but due to chronic stimulation become increasingly pro-inflammatory with disease progression. Figure was created with the help of BioRender.com